Abstract
Persistent macrophage activation is associated with the expression of various pro-inflammatory genes, cytokines and chemokines, which may initiate or amplify inflammatory disorders. A novel synthetic BET inhibitor, JQ1, was proven to exert immunosuppressive activities in macrophages. However, a genome-wide search for JQ1 molecular targets has not been undertaken. The present study aimed at evaluating the anti-inflammatory function and underlying genes that are targeted by JQ1 in LPS-stimulated primary bone marrow-derived macrophages (BMDMs) using global transcriptomic RNA sequencing and quantitative real-time PCR. Among the annotated genes, transcriptional sequencing of BMDMs that were treated with JQ1 revealed a selective effect on LPS-induced gene expression in which the induction of cytokines/chemokines, interferon-stimulated genes, and prominent (transcription factors) TFs was suppressed. Additionally, we found that JQ1 reduced the expression of previously unidentified genes that are important in inflammation. Importantly, these inflammatory genes were not affected by JQ1 treatment alone. Furthermore, we confirmed that JQ1 reduced cytokines/chemokines in the supernatants of LPS treated BMDMs. Moreover, the biological pathways and gene ontology of the differentially expressed genes were determined in the JQ1 treatment of BMDMs. These unprecedented results suggest that the BET inhibitor JQ1 is a candidate for the prevention or therapeutic treatment of inflammatory disorders.
Highlights
Pathogen infection clearance and in regulating tissue repair and recovery, excessive or persistent activation of these innate immune cells contributes to the pathogenesis of both metabolic and inflammatory disorders[6]
Previous studies demonstrated that abundant pro-inflammatory cytokines can result in excessive inflammation and tissue damage, which contributes to inflammatory disorder pathogenesis[10]
We performed gene array and comparative gene expression profiling analyses of BMDMs that were treated with LPS, JQ1 or LPS + JQ1 using RNA sequencing (RNA-seq), a precise technique that is increasingly being used to study gene expression, as it provides unbiased profiles and the ability to identify novel transcribed regions compared with microarrays and can be extremely accurate if a sufficient level of coverage is obtained[19,20]
Summary
Pathogen infection clearance and in regulating tissue repair and recovery, excessive or persistent activation of these innate immune cells contributes to the pathogenesis of both metabolic and inflammatory disorders[6]. The inhibitor represses downstream gene expression by competitively binding to BET proteins and displacing BET proteins from acetylated lysines on chromatin These proteins emerged as attractive therapeutic targets in the treatment of inflammation and cancer[12,13]. JQ1 was shown to control the expression of numerous genes involved in the cell cycle, cell growth, inflammation and cancer, which suggests that the products of these genes function as epigenetic signalling proteins that regulate transcription in a cell context-dependent manner[14,15] These outcomes indicate the possibility of using JQ1 as a potential therapeutic target for modulating gene expression programs that are associated with a diverse range of pathologies, predominantly cancer and inflammatory diseases. These findings establish a role for BET proteins in mouse macrophage stimulation and justify further testing of BET protein-targeting genes in inflammatory disorders
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